Sharpening the cutting edge: additional considerations for the UK debates on embryonic interventions for mitochondrial diseases

One of the most prominent gaps in the UK debates of mitochondrial interventions was the absence of consideration of other reproductive possibilities available to affected women, accompanied by a failure to weigh, systematically, the costs and benefits of each option against the others. Instead the new science of mitochondrial intervention was the starting point for deliberation and was presented in some quarters as the only desirable way in which women with faulty mitochondria could have healthy babies. The alternatives of ‘traditional’ full egg donation,⁶ surrogacy with egg donation, or adoption, were rarely discussed, let alone given detailed or informed consideration. For example, even an organisation as well versed in assisted conception as the HFEA made no reference, in its advice to Government resulting from its public consultation, to these other ways that affected women could have a healthy child. This suggests that these alternatives were not prominent in their deliberations or in the consultation processes (HFEA 2013).

Such opening statements set the terms for these debates and thereby limited the opportunity to debate alternative approaches, by establishing the view that genetic relatedness was a key consideration driving the development of the techniques.

A Daily Mail article reported that ‘Women carrying damaged mitochondria can also miscarry repeatedly and often face the heartbreaking choice of whether it would be best to remain childless’ (Macrae 2014). Neither of these pieces (typical of the many published) mention the alternative routes that affected women could take to become mothers of healthy children, again reinforcing the assumed importance of the genetic connection sustained by PNT/MST. The Macrae article also raised the notion of ‘choice’ which was common in many contributions to these discussions. When questioned on the possibility of using non-PNT/MST methods to conceive, an affected woman interviewed on a BBC national news programme on the day of the House of Commons debate, said that the mitochondrial techniques would give her, and women like her, ‘choice’. She did not expand on that though the insinuation within the context of the discussion was that this is the choice to have a genetically related baby; this was not pursued by the interviewer, as if ‘choice’ in and of itself was an unquestioned value.

This emergence of the language of choice and consumerism in the discourse around health care provision in the early 2000s coincided with the long period of development of PNT/MST (Fotaki, 2010, 898). Nonetheless, in the context of the radio interview and other discussions around mitochondrial interventions, the notion of ‘choice’ was used to close down consideration of existing alternatives and to promote the new interventions, by those who were advocates for the science and by those who prioritised genetic relatedness between parents and children. Genuine discussion of choice in conception and reproduction (and more generally) would clearly have been an important aspect to add to these debates, given that families in twenty-first century UK are composed of individuals with a diverse range of genetic relationships, or none at all.

As fundamental as the question, ‘what alternatives are available?’ is the question, ‘how safe is the proposed new intervention?’ Questions of the safety of PNT/MST were addressed by a Safety Review Panel (hereafter, the Panel) convened by the HFEA, to ‘review the latest evidence of safety and efficacy’ (HFEA 2014, 9).

Clearly the argument that it cannot be fully known whether new treatments are safe until they are tried in human beings is correct but it is questionable whether the appropriate comparator was addressed by the Panel. Medicines or medical devices that do not behave as safely as expected might well affect the first individuals to receive them, but PNT/MST are interventions of a different order, with the potential to affect the whole human species, rather than a series of individuals, because they change the germline. Given that there are existing alternative ways for affected women to try to conceive, it can be argued that a stronger indication of safety should have been required for the introduction of the new techniques.

St John (2014) identified the need to avoid any transfer of damaged mitochondria from the affected woman’s egg, and the practical difficulty of doing so, describing animal experiments that have shown the persistence of damaged mitochondria. He also raised concerns about epigenetic effects and mismatching of nuclear and mitochondrial DNA.

Clearly, issues about the safety of any intervention cannot be neatly distinguished from socio-ethical concerns, not least because it can never be morally correct to offer interventions that are known to be unsafe, except under exceptional circumstances and where no alternatives exist. On the more general point, there is also not as clear a divide between science and values as some contributors suggested: as we have seen above, PNT/MST are partly being offered in the first place because of the largely unstated valorisation in the scientific literature of genetic ties between parents and children. The vast literature from Science and Technology Studies identifies the numerous ways in which ‘science’, far from being an external source of objective knowledge, is inextricably shaped by, and shapes, wider social values, institutions and processes (e.g. Jasanoff 2004).

It is worth noting that papers published since the 2015 UK legislation indicate that earlier concerns about the safety of PNT/MST are justified. Callaway (2016) reports that work carried out by Egli’s group in New York (Yamada et al. 2016) found, as Knoepfler feared, that small amounts of the intending mother’s damaged mt-DNA might be carried over and ‘outcompete healthy mitochondria in a child’s cells and potentially cause the disease [that] the therapy was designed to avoid’. Further evidence of this phenomenon was reported in Nature in November 2016 (Kang et al. 2016; Cook 2016b). Egli argued that this problem would ‘defeat the purpose of doing mitochondrial replacement’ and recommended that the procedure not be used in the meantime, arguing ‘I don’t think it would be a wise decision to go forward with this uncertainty’ (quoted in Callaway, 2016).

A facet of the discussion that made such a political decision possible was the clear focus on babies and children, and on the most severe forms of mitochondrial diseases, by the mass media and patient advocacy groups. This is rather misleading since many mitochondrial diseases only manifest themselves in adults and have varying degrees of severity (NCoB 2012, Dimond 2015). It would have been more transparent (and the calculations of the numbers of affected persons would be higher) if the case in favour of allowing these techniques had reflected the full range of affected persons.

It could be argued that the devastating conditions that affect babies and young children are predominantly the conditions that the proposed techniques will be used to prevent. However, the women who are the targeted beneficiaries of PNT/MST have mitochondrial disease themselves and yet have a quality of life that has enabled them to get to the point of wanting to start a family; this is an indication that the impact of mitochondrial diseases is much more variable than presented in the debates. Therefore the focus on babies and children was a missed opportunity to raise awareness of the full range of mitochondrial diseases, and their manifestations, and of the differing experiences of living with such conditions.

The lack of clarity about the range of conditions that will be valid targets for attempts to prevent transmission from mother to child is evident; the overall impression is that all mitochondrial diseases will be prevented.

The conflation of ‘mitochondrial disease’ with specific serious mitochondrial diseases caused by mt-DNA mutations, plus the lack of clarity that ensues from the conflation of ‘preventing transmission’ with the numbers of children estimated to be affected by all mitochondrial diseases, results in the inflation of hope and expectation for the proposed interventions; not least expectations about the public health impact of permitting PNT/MST.

The Parliamentary Under-Secretary of State for the Department of Health, when opening the Lords debate, said ‘the DNA from the donor egg amounts to less than 1% of the resulting embryo’s genes’ and that ‘One important point to emphasise here is that none of the nuclear DNA, which determines our personal characteristics and traits, is altered by mitochondrial donation.’ (Hansard 2015b: Col 1569). Other examples abound. This is not the place to enter into argument with the claim that nuclear DNA ‘determines’ personality, other than to note that the presence or absence of mitochondrial disease is likely to have a profound impact on an individual’s personality (NCoB 2012; Baylis 2013; Haimes and Taylor 2015). More important to note for our analysis here is the way in which claims about the tiny portions of donated mt-DNA are configured. The implication of this repeated refrain is that, because the numbers being discussed are so small, the genetic material to which they refer is unimportant and insufficient to provoke concern. And yet, without these tiny amounts of mt-DNA, an affected woman would have no hope of bearing a healthy, genetically-related child – which of course is the whole point of these discussions in the first place. Minimising the contribution of the mitochondrial genome in numerical terms means that the proponents of the techniques were making paradoxical claims: saying these interventions and therefore these genes are both crucial (to prevent transmission of mitochondrial diseases) but are also essentially insignificant because they are only few in number. The insinuation is that opposing an intervention which involves such a small amount of genetic material could be nothing but unreasonable.

Just as numerical calculations were deployed to minimise and deflect concerns about the proposed interventions, they were also deployed to strengthen the case in favour of these interventions, albeit in confusing and inconsistent ways.

Using publicly available information, we can use these figures to estimate that around 5280 adults in the UK are affected by mt-DNA diseases.¹¹ However, until 2015, the number of families to be treated through PNT/MST per year was often cited in debates as ‘around 10’ (for example (BBC 2013), Sample (2013)) though it is unclear from whence this figure originated. Just before the 2015 House of Commons debate, the Newcastle Group estimated that the ‘average number of births per year among women at risk for transmitting mtDNA disease’ was 152, from a population of 2473 affected women in the UK suggesting that in the future about 150 births per year could potentially benefit ‘if all women opted for the procedure’ (Gorman et al. 2015, 886-7). Again, using publicly available figures and an alternative approach to estimating the number of women who might be able to benefit from PNT/MST, it is possible to estimate that the number of children born each year who may be affected by serious mitochondrial disease is between 112 and 148.¹² (See also Herbrand 2016).

While 10 cases per year might be manageable, the question of how the HFEA would deal with up to 150 cases per year was not part of the wider discussions. When asked a question¹³ about the possibility of 150 cases coming forward per year, the Chair of the HFEA echoed the claim that only around 10 applications were expected per year and that the Authority had the resources to cope with that number. No acknowledgement was made that the higher figure might be possible. It is a moot point as to what impact the higher numbers had on the views of Parliamentarians, but clearly the higher figures could be deployed to make the case that PNT/MST interventions are much needed, while the lower number was deployed to reassure all parties that regulatory oversight could and would be provided. Whatever the baseline figures, the work for the HFEA may be increased given the recent recommendation from the Newcastle Group that PNT should only be used in conjunction with embryo screening (Hyslop et al. 2016).

As we have detailed elsewhere (Haimes and Taylor 2015) the discussion of the egg providers (for both research and treatment), and the terminology used to describe them in the debates, was problematic. Little, if anything, was said about the role and contributions made by these women. Indeed it appears that their role was deliberately minimised: for example, the NCoB argued they should not ‘be given the same status in all aspects of regulation as a reproductive egg or embryo donor’ (2012, para 5.3) and the HFEA ‘Advice to Government’ reduced their status to that of mere ‘tissue donors’ (2013, para 1.13). The commitment of time, energy and generosity required from the egg providers and the invasiveness of the procedure through which the eggs are produced and collected for use in research or treatment were all but ignored. (For further discussion see Baylis 2013, Haimes 2013, Haimes and Taylor 2013).

While an acknowledged opponent of embryo research in general, Bruce here is expressing concerns that Parliament would (and did) vote on the legislation with incomplete understanding of the safety of PNT/MST and therefore with an incomplete understanding of the possible long-term consequences for the affected women and any offspring they may have through using these techniques.

This means that it would only have been two to three years before the health of any offspring from the female Macaque could be established and therefore any long term negative consequences detected. Some Parliamentarians, such as Bruce above, clearly thought that waiting until these (and other) safety experiments had been completed would have been prudent. Therefore, within the terms of existing and imminent knowledge within the field, it could be argued that there was an over-hasty move to legislation.

Similarly, Petrini and Ricciardi (2015) describe the need for ‘the balancing of individual rights and collective interests, which are often in conflict’ (2015, 270). It could be argued that legalising PNT/MST operates in an inverse manner to public health measures such as vaccination, which requires that parents take a risk with their child for the benefit of the population (Wood-Harper 2005) since the former entails taking a risk with the future of the population, through the unknown and irreversible consequences of modifying the germline, in favour of the immediate, hoped-for benefits to individual families.¹⁵

Other jurisdictions might appreciate the usefulness of a more fully rounded debate. As Bredenoord and Hyun (2015) argue, when discussing whether the USA should follow the UK’s lead in permitting MST/PNT, ‘The bold leap from bench to bedside needs sufficient preclinical evidence and careful, long-term interdisciplinary research, including more ethics research’ (2015, 976). They recommend that the USA should take a more cautious path and argue, ‘A cautionary approach means that a wide variety of concerns should be taken seriously – wider than safety and efficacy alone’; the need is to find a balance between ‘taking appropriate precautions and not unnecessarily hampering innovation’ (2015,976). The US National Academies of Science, Engineering and Medicine report on mitochondrial disease (National Academies of Sciences, Engineering, and Medicine 2016) describes these interventions as raising ‘a novel collection of ethical, social and policy issues’ (2016, xiii). The starting point for their deliberations was ‘parental motivation’ for using these techniques in light of ‘alternative approaches to creating families’ and the ‘primary value’ to be considered when balancing risks and benefits of further clinical investigations was ‘minimizing the risk of harm to the child born as a result’ (2016, xv). They concluded that it is ethically permissible to conduct clinical investigations of these interventions but with two major restrictions: that investigation should be limited to women at risk of transmitting a serious mitochondrial disease and that only male embryos are transferred for gestation, ‘to avoid introducing heritable genetic modification during initial clinical investigations’. (2016, xv). While this second restriction raises its own ethical challenges in creating ‘experimental offspring’ (Taylor and Haimes 2012, NCoB 2012, 80), the USA is clearly taking more time to reach a decision and appears unlikely to follow the same path as the UK.

As we have shown, many important areas were neglected in the UK debates and the claims about the quality of those debates are over-stated. It is impossible to say what the outcome of the debates would have been had these more nuanced discussions been included. What we can suggest is that by leading the argument in the way that they did, focussing on the emotive and profoundly distressing effects of mitochondrial disease on babies, children and their families, and by failing to address a range of other issues in detail, the proponents of the technology leave themselves open to challenge in the future should the techniques fail to have as powerful an impact on mitochondrial diseases as some parties to the debates clearly expect them to have, or prove to be unsafe, or lead to other (perhaps more commercial and exploitative¹⁶) uses being approved.

The analysis presented here provokes the question of where the UK stands on the global stage in relation to mitochondrial interventions. Clearly the scientific endeavour in the UK is at the cutting edge of progress in this field. However, given that the UK legislation is the first example of the permissibility of genetic modification of human beings, and given the more cautious approach recommended for, and being taken by, the USA and Australia (de Lacey 2016), it could be argued that the UK is precariously out on a regulatory limb,¹⁷ until the many aspects discussed in this article are more clearly understood.